Epigenetic gene silencing associated with promoter hypermethylation is now recognized as a fundamentally important mechanism of gene inactivation in cancer. While this is an important mechanism for disabling known tumor suppressor genes, identification of hypermethylated alleles in cancer also offers a novel approach for gene discovery. HIC1 (Hypermethylated In Cancer 1), a POZ domian zinc finger transcriptional represser, was identified in a screen for hypermethylated alleles in chromosome 17p13.3. Epigenetic silencing of HIC1 is a frequent event in human cancer, and mice heterozygous for Hid develop cancers associated with hypermethylation of the wild type allele. However, the functions of this gene as a tumor suppressor, and in a broader biological context, are unknown. HIC1 has emerged as a potential important tumor suppressor in medulloblastoma, a primitive embryonal tumor arising from the granule cell precursors of the cerebellum which serves as an important model of neural differentiation as it relates to tumorgenesis. Medulloblastoma is a highly aggressive perdiatric malignancy in which key tumor suppressor genes are yet to be identified. Our preliminary data in genetic mouse models, and in human medulloblastoma, suggest a critical role for HIC1 in neural differentiation and tumor suppression in the CNS through transcriptional repression of key neural development genes. We propose that functional analysis of HIC1 in both neural development and medulloblastoma will provide critical insights into how failure of neural differentiation may promote cerebellar neoplasia through inappropriate persistence of signaling pathways normally required in the earliest stages of neural development. The central hypotheses of this proposal are (1) that HIC1 is a transcriptional represser required for neural differentiation, and (2) epigenetic silencing of the HIC-1 plays a critical role in the development of medulloblastoma. We propose to explore these hypotheses in two novel genetic mouse models, as well as human and murine medulloblastoma cells. Relevance to public health: Using a mouse brain tumor model, we will investigate how a new human tumor suppressor genes functions to prevent cancer by understanding how it regulates brain development through control of gene exression. These findings are of direct relevance to many cancers, since deregulation of pathways known to be important in embryonic development can help us understand the basis of human malignancy.